G protein-coupled receptors (GPCRs) class is the largest family of cell-surface receptor which plays a crucial role in intracellular signal transduction. Adenosine receptors are part of the GPCR class, which belongs to the Class A or rhodopsin-like subfamily of GPCRs. Adenosine is a naturally occurring nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors known as A1, A2a, A2b, and A3, which are involved in numerous physiological and pathophysiological processes (See Fredholm et al., Pharmacol. Rev. 2001, 53, 527-552).
Adenosine A1 and A2 receptor agonists, most derived from adenosine, have been intensively studied for use as hypotensive agents, therapeutics for mental illness and arrhythmia, lipid metabolism suppressant (therapeutics for diabetes) and neuroprotectives. On the other hand, their antagonists, derived from xanthine or in the form of two or more fused heterocyclic compounds, are developed as anti-asthmatics, anti-depressants, anti-arrhythmics, renal protectants, drugs for Parkinson's disease, and intelligence enhancers (See U.S. Pat. No. 9,018,371).
The function of the adenosine A3 receptor was the most recently identified, in contrast to the A1 and A2 receptors. The A3 receptor inhibited adenylyl cyclase, an enzyme that produces cAMP from ATP. Also, when activated by agonists, the A3 receptor was proven to mediate the activation of guanosine triphosphate-dependent phospholipase C, an enzyme which catalyzes the degradation of phosphatidyl inositol into inositol triphosphate and diacylglycerol (DAG) in the brain (See Ramkumar, V. et al., J. Biol. Chem., 1993, 268, 168871-168890; Abbracchio, M. P. et al., Mol. Pharmacol., 1995, 48, 1038-1045). On the other hand, the inactivation of A3 adenosine receptor causes the release of inflammation factors, such as histamine, from mast cells, bronchoconstriction, and the apoptosis of immune cells. Thus, A3 adenosine receptor agonists are under consideration in the treatment of cardiac and cerebral ischemia and cancer, while A3 adenosine receptor antagonists have been suggested to be useful as a potential treatment for glaucoma, inflammation and asthma (See U.S. Pat. Nos. 6,066,642 and 6,528,516 and WO 2008/055711).
Glaucoma remains one of the leading causes of irreversible blindness worldwide, afflicting approximately 70 million people. Elevated Intraocular Pressure (TOP) has been demonstrated as a major risk factor for the development and progression of glaucoma, through a number of well-conducted, prospective, randomized clinical trials that have provided overwhelming evidence that IOP reduction effectively slows the rate of development or progression of visual loss caused by glaucoma. However, available pharmacological and surgical therapies have limited efficacy and significant side effects (See Medeiros, F. A. et al., Drugs Today 2002, 38, 563-570). Most adverse effects associated with IOP-lowering medications are mild and ocular in nature; however, several of them are associated with systemic risks as well as serious ocular effects, especially following chronic use (See Schuman, J. S. et al., Expert Opin. Drug Saf 2002, 1, 181-194).
Adenosine levels have been found to be elevated in the aqueous humor of ocular hypertensive patients, and A3ARs are substantially upregulated on nonpigmented ciliary epithelial (NPE) cells in patients with pseudoexfoliation syndrome. The A3AR holds promise in glaucoma because knockout of the A3AR reduces IOP in the living mouse and A3AR antagonists have been shown to reduce IOP in rodents, rabbits, and both normal and glaucomatous monkey (See Avila et al., Investig. Ophthalmol. Vis. Sci., 2002, 43, 3021-3026). A3AR antagonists physiologically decrease inflow of aqueous humor by inhibiting Cl— channels of the NPE at the aqueous surface. It has also been observed that antagonists of A3AR are neuroprotective to oxygen and glucose deprived hippocampal tissue. A3AR are present on retinal ganglion cells and antagonists of the A3AR have the potential to be neuroprotective in patients with glaucoma.
Currently, none of the existing medical or surgical therapies protect the retina from degeneration in glaucoma.